Induction of immune tolerance is a powerful tool to control immune responses responsible for pathological situations. Cytokines, enzymes controlling metabolic pathways and cell surface molecules capable of inducing tolerance have been described. Despite these findings, evidence for other non-identified mechanisms exists and is thus important to identify new mediators of immune tolerance.
Organ transplantation has shown very significant improvements in both prevention and treatment of acute rejection but subclinical episodes and chronic graft dysfunction still heavily impact medium and long-term graft survival (1). Emerging therapeutic strategies, among them tolerance induction to donor antigens are moving into the clinics after years of experimental models work (2, 3). Among natural mechanisms and tolerance inductive strategies, different types of regulatory cells are among the most promising ones (4). CD8+ regulatory T cells (CD8+ Tregs) in the transplantation field but also in other pathophysiological situations have been highlighted in recent years (5-8). Cytokines, enzymes controlling metabolic pathways, and cell surface molecules, capable of inducing tolerance, have also been described as new mediators of immune tolerance.
A new cytokine called IL-34 was identified in 2008 (9). Studies showed that IL-34 shares homology with M-CSF and acts through a common receptor, CD115 also called CSF-1R (9) expressed on the cell surface of monocytes, and in the brain through a new described receptor, Receptor-type Protein-tyrosine Phosphatase ζ (PTP-ζ) (10). However, studies have demonstrated that IL-34 and M-CSF displayed distinct biological activity and signal activation (11), probably due to differential spatial and temporal IL-34 and M-CSF expression (12). IL-34 function has been mainly related until now with monocytes and macrophages (osteoclasts, microglia), as well as DCs, survival and function (12). Datas on the expression of IL-34 in resting cells were partially overlapping since mice with GFP under the control of the IL-34 promoter showed positive keratinocytes, hair follicles, neurons, proximal renal tubule cells and seminiferous tubule germ cells (12), whereas mRNA and protein analysis showed heart, brain, lung, liver, kidney, spleen, thymus, testicles, ovaries, prostate, colon, and small intestine, and abundant protein expression in spleen red pulp and osteoclast (9). Upon inflammation, other cells such as fibroblasts (13), osteoclasts (14) and articular synovial cells (13) upregulated IL-34 expression. So far, expression of IL-34 by other lymphoid cells and particularly T cells has not been described or demonstrated. Similarly, IL-34 has not been linked to effects on immune function of DCs or T cells since the decreased response to DTH antigens or CNS viral infections in IL-34-deficient mice was linked to paucity of Langerhan's and microglia, in skin and CNS respectively (12). Finally, there is no description to date of a role for IL-34 in tolerance in transplantation.
In a model of cardiac allograft in rats, it has been previously shown that blocking of CD40-CD40L, by CD40Ig treatment, induces long term graft survival through generation of of CD8+CD45RClow Tregs (termed CD8+CD40Ig Tregs) (15). It also been showed that these CD8+ Tregs impose allogeneic tolerance partially through production of IFNγ and fibrinogen-like protein 2 (FGL2) (15, 16), and recognition of a dominant MHC-II-derived donor peptide (17). A potential role for FGL2 as an immune tolerogenic mechanism was first suspected when pan-genomic transcriptomic comparison of CD8+CD40Ig Tregs vs. CD8+CD45RClow Tregs from naïve rats showed increased FGL2 expression (16). The same transcriptomic analysis revealed that IL-34 was overexpressed in in CD8+CD40Ig Tregs from long-term recipients vs. CD8+CD45RClow Tregs from naive animals.
Therefore, despite considerable advances in prevention of transplant rejection, such pathology remains associated with high morbidity and mortality and there is a desperate need for new mediators of immune tolerance and new tolerance inductive strategies (more particularly by down-regulating T-cell responses) for use in the prevention or the treatment of transplant rejection (or for use in the induction of transplant tolerance) as well as autoimmune disease, unwanted immune responses against proteins expressed in the course of gene therapy and/or therapeutic proteins and allergy.
Moreover, there is a need for an easily measurable biomarker predicting the risk of transplant rejection. Such a biomarker would thus be useful for monitoring transplanted patients and also adjusting their immunosuppressive treatment.
Until now, no study has examined whether IL-34 might induce immune tolerance and predict whether a transplanted patient is tolerant or not (displaying thus an increased risk of transplant rejection and therefore requiring an appropriate immunosuppressive treatment). Similarly, IL-34 has not been linked to effects on immune function of DCs or T cells and its suppressive potential in transplantation has never been suspected and studied.